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Proliferative and Nonproliferative Lesions of the Rat and Mouse Hepatobiliary System

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Proliferative and Nonproliferative Lesions of the Rat and Mouse Hepatobiliary System Toxicologic Pathology, 38: 5S-81S, 2010 Copyright # 2010 by The Author(s) ISSN: 0192-6233 print / 1533-1601 online DOI: 10.1177/0192623310386499 Proliferative and Nonproliferative Lesions of the Rat and Mouse Hepatobiliary System 1 2* 3 4 5 6 BOB THOOLEN ,ROBERT R. MARONPOT ,TAKANORI HARADA ,ABRAHAM NYSKA ,COLIN ROUSSEAUX ,THOMAS NOLTE , 7 8 9 10 11 12 DAVID E. MALARKEY ,WOLFGANG KAUFMANN ,KARIN KU¨ TTLER ,ULRICH DESCHL ,DAI NAKAE ,RICHARD GREGSON , 13 14 15 16 17 MICHAEL P. VINLOVE ,AMY E. BRIX ,BHANU SINGH ,FIORELLA BELPOGGI , AND JERROLD M. WARD 1Global Pathology Support, The Hague, The Netherlands 2Maronpot Consulting LLC, Raleigh, North Carolina, USA 3The Institute of Environmental Toxicology, Joso-shi, Ibaraki, Japan 4Haharuv 18, Timrat, Israel 5Wakefield QC, Canada 6Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany 7National Toxicology Program, Cellular and Molecular Pathology Branch, Research Triangle Park, North Carolina, USA 8Merck KGaA, Darmstadt, Germany 9BASF Aktiengesellschaft, Ludwigshafen, Germany 10Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/Riss, Germany 11Tokyo Metropolitan Institute of Public Health, Shinjuku, Tokyo, Japan 12Charles River Laboratories, Pathology Department, Senneville, QC, Canada 13Pathology Associates, Charles River, Frederick, Maryland, USA 14Experimental Pathology Laboratories Inc., Research Triangle Park, North Carolina, USA 15DuPont Haskell Global Centers for Health and Environmental Science, Newark, Delaware, USA 16Ramazzini Institute, Bentivoglio (BO), Italy 17Global VetPathology, Montgomery Village, Maryland, USA *Chairman of the Liver INHAND Committee ABSTRACT The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an interna- tionally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature and differential diagnosis for classifying microscopic lesions observed in the hepatobiliary system of laboratory rats and mice, with color microphotographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available for society members electronically on the internet (http://goreni.org). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for lesions of the hepatobiliary system in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists. Keywords: diagnostic pathology; hepatobiliary system; histopathology; liver; nomenclature; rodent pathology. Address correspondence to: Bob Thoolen, Global Pathology Support, Benoordenhoutseweg 23, The Hague 2596 BA, Netherlands; e-mail: bob.thoolen@ gpstoxpath.com. Financial Disclosure: No money was paid for the preparation of this manuscript. During the construction of this manuscript salaries of contributors were paid by their respective companies. None of the content of the manuscript contains any information that could be patentable or claimed as intellectual property of the contributors or their respective companies. Abbreviations: AE1/AE3, Two clones of anti-cytokeratin monoclonal antibodies; a.k.a., Also known as; AS, Anterior Segment; a-SMA, a-smooth muscle actin; Bcl-2, B-cel lymphoma 2 - apoptosis regulator protein; BSTP, British Society of Toxicological Pathologists; CD (31, 34, 68), Cluster differentiation (31, 34, 68); CEA, Carcinoembryonic antigen; CK, Cytokeratin; ED1, Rat homologue of human CD68; EM, Electron microscopy; ESTP, European Society of Toxicologic Pathology; Factor VIII, Blood clotting factor/anti-hemophilic factor; F4/80, Rat anti-mouse macrophage monoclonal antibody; H&E, Hematoxylin and Eosin; IHC, Immunohistochemistry; JSTP, The Japanese Society of Toxicologic Pathology; Ki-67, Nuclear protein associated with proliferation; LAMP, Lysosome- associated protein; LLL, Lef lateral lobe; LML, Left medial lobe; MIB-1, Monoclonal antibody that detects K-67 antigen on formalin fixed paraffin embedded sections; MS, Middle Segment; NTP, National Toxicology Program; NLDC-145, Rat anti-mouse dendritic cell monoclonal antibody; NOS, Not otherwise specified; OX-6, MHC Class II Ia antibody; PAS, Periodic acid-Schiff; PC, Caudate Process; PCNA, Proliferator Cell Nuclear Antigen; PCR, Polymerase Chain Reaction; PP, Papillary Process; PPA, Processus papillaris anterior; PPAR, Peroxisome Proliferator-Activated Receptor; PS, Posterior Segment; RER, Rough Endoplasmic Reticulum; RLL, Right lateral lobe; RML, Right medial lobe; SRA-E5, Mouse monoclonal anti-macrophage antibody for Scavenger Receptor A; SOPs, Standard Operating Procedures; STP, Society of Toxicologic Pathology. 5S Downloaded from tpx.sagepub.com at Society of Toxicologic Pathology on May 21, 2015 6S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY TABLE 1.—Species differences in liver lobes. Human (4 / 8)a Monkey (4 / 8) Dog (6 / 7) Rat (4 / 7) Mouse (4 / 7) Cat (6 / 7) Left liver Left Lobe (2 segments) Left (lateral) Lobe Left Lobe Left Lobe Left Lobe Left Lobe LLL AS þ PS LLL þ LML LLL þ LML LLL þ LML (largest) þ LML Right liver Right Lobe (2 segments) Right (lateral) Lobe Right Lobe RLL Right Lobe Right Lobe Right Lobe AS þ MS þ PS (impression) þ RML RLL þ RML RLL þ RML RLL þ RML Intermediate liver Quadrate Lobe Median Lobe (largest) Quadrate Lobe Quadrate Lobe Quadrate Lobe (small) Caudate lobe Caudate Lobe Caudate Lobe Caudate Lobe Caudate Lobe Caudate Lobe Caudate Lobe PC þ PP PP þ PC PP þ PPA þ PC PP þ PC PP þ PC LLL ¼ Left lateral lobe; RLL ¼ Right lateral lobe; PC ¼ Caudate Process; LML ¼ Left medial lobe; RML ¼ Right medial lobe; PP ¼ Papillary Process; PPA ¼ Processus papillaris anterior; AS ¼ Anterior Segment; MS ¼ Middle Segment; PS ¼ Posterior Segment. Gray, Williams, and Bannister (1995); Browning, Schroeder, and Berringer (1974); Ko¨nig, Sautet, and Liebich (2004); Rajtova´, Hora´k, and Popesko (2002); Vons et al., 2009. a (Number of lobes / Number of lobes including segments). I. GENERAL INTRODUCTION frequently observed in pathological evaluation of toxicity studies. The liver is a major target organ in safety assessment of preclinical toxicity and oncogenicity studies with rodents; hence, hepatic pathology is central to many toxicological II. ANATOMY pathology studies. As toxicologic pathologists sometimes The liver occupies the cranial third of the abdominal experience difficulties in distinguishing the wide variety of cavity and is comprised of multiple lobes; however, the liver lesions in the rodents for safety evaluation purposes, this nomenclature for the liver lobes varies among authors. There document is a consensus of senior toxicologic pathologists are basically left, middle, right,andcaudate lobes (Harada regarding suggested nomenclature that should be used for et al. 1999; Eustis et al. 1990). A thin connective tissue cap- specific lesions. sule that is externally lined by peritoneal mesothelial cells Standardized diagnostic criteria and nomenclature are covers the parietal and visceral surfaces of the liver. The essential to harmonize the classification and reporting of hepa- middle lobe has an incomplete fissure where the falciform tic nonproliferative as well as proliferative lesions. This ligament attaches. In mice the gallbladder is located in the INHAND document serves as a framework that can be used for middle lobe fissure, whereas the rat does not have a gallblad- the harmonization of diagnostic criteria of hepatic lesions in der. The right lobe has an anterior and posterior component laboratory rats and mice. These recommendations for diagnos- and the small caudate lobe consists of two or more disc- tic criteria and preferred terminology should not be considered like sublobes (See Figure 1). mandatory; proper diagnoses are ultimately based on the dis- Nomenclature for liver lobes varies among species and cretion of the toxicologic study pathologist. sometimes among authors. A table showing differences in liver The INHAND (International Harmonization of Nomenclature lobes between species is included based on current anatomic and Diagnostic Criteria for Lesions in Rats and Mice) initiative features (Table 1). creates a framework for the harmonization of diagnostic nomen- clature (classification of lesions using the same terminology) in III. HISTOMORPHOLOGY different rodent organ systems. It is a joint initiative between Societies from the United States (STP), Great Britain (BSTP), The two-dimensional microarchitecture of the liver has Japan (JSTP), and European countries (ESTP). been categorized in at least three perspectives (Figure 2). The This document is organized to provide introductory material anatomic model is the classical lobule, a hexagonal structure that reviews comparative interspecies differences in anatomy divided into concentric centrilobular, midzonal, and peripor- and liver function, followed by a listing of liver lesions in a tal segments. The triangular portal lobule is based on bile standardized
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